It is known that transitions between phases of the cell cycle are catalyzed by a family of cyclin-dependent kinases (Nurs, 1990; Hartwell et al., 1974). In many cells, transit through G1 of the cell cycle and entry into S phase requires a binding and activation of cyclin/cyclin-dependent kinase complexes (CDK), predominantly cyclin D-cdk4,6 and cyclin E-cdk2 (Sherr, 1994; Sherr, 1996).
The cyclin-dependent kinase inhibitors (CKIs) are naturally-occurring gene products which inhibit cyclin-CDK activity and phosphorylation of retinoblastoma protein (Rb), resulting in G1/S growth arrest (D. O. Morgan, 1995; Sherr and Roberts, 1995). CKIs directly implicated in CDK regulation are p21cip1/Waf1 (Xiong et al., 1993; Harper et al., 1993), p27Kip1 (Pyoshima and Hunter, 1994; Polyak et al., 1994; Coats et al., 1996), and p16/p15INK4 (Serrano et al., 1993).
The ability of CKIs to arrest cells in G1 have made the proteins of particular use in gene therapy techniques for treating diseases or disorders associated with cell proliferation, such as cancer and leukemias, psoriasis, bone diseases, fibroproliferative disorders, atherosclerosis, restenosis, and chronic inflammation. However, very little is known about the regulation of these very important proteins in vivo.